膝關節骨關節炎的治療

2021-02-14 杭州胡金艮大夫

翻譯:朱錦宇

專題提綱

總結與推薦

引言

定義

一般原則

根據臨床表現選擇治療方法

輕度膝關節OA

中/重度膝關節OA

OA僅累及膝關節或同時累及其他關節

有共存疾病的患者

輕度膝關節OA

局部用NSAID

局部用辣椒鹼

鍛鍊

減輕體重

初始非藥物治療措施

非藥物治療的效果不充分

中/重度膝關節OA

無效或益處不明的療法

鞋墊

氨基葡萄糖和軟骨素

其他營養補充劑

阿片類物質

透明質酸

富血小板血漿

對乙醯氨基酚

經皮神經電刺激

針刺

局部熱療

學會指南連結

總結與推薦

參考文獻

相關專題

患者教育：關節炎和鍛鍊(基礎篇)

患者教育：骨關節炎(基礎篇)

成人未分類膝關節疼痛的評估

成人疑似肌肉骨骼性膝關節疼痛的評估方法

成人肥胖：治療概述

草藥和膳食補充劑的肝毒性

阿片類藥物用於治療慢性非癌症疼痛

骨關節炎的臨床表現和診斷

骨關節炎的發病機制

骨關節炎的在研管理方案

骨關節炎的流行病學和危險因素

骨關節炎管理概述

Acupuncture

Comorbidities that impact management of osteoarthritis

Management of moderate to severe knee osteoarthritis

Patient education: Arthritis and exercise (Beyond the Basics)

Patient education: Osteoarthritis symptoms and diagnosis (Beyond the Basics)

Patient education: Osteoarthritis treatment (Beyond the Basics)

Society guideline links: Osteoarthritis

引言膝關節骨關節炎(osteoarthritis, OA)的循證治療方法包括非藥物治療、藥物治療和手術，旨在緩解疼痛、改善關節功能以及改變骨關節炎進展的危險因素。儘管研究者們做出了較大努力，但旨在改變疾病病程的療法效果仍欠佳，尚未獲得監管機構的批准。

多種機制可引發疼痛，全面評估患者是治療膝關節OA的一個重要部分。此外，具體的患者和疾病特徵通常也會影響臨床決策制定。本專題將總結膝關節OA的治療，尤其是輕度膝關節OA的治療。關於OA和膝關節疼痛的其他相關專題包括：

●(參見「骨關節炎的發病機制」)

●(參見「骨關節炎的流行病學和危險因素」)

●(參見「骨關節炎的臨床表現和診斷」)

●(參見「骨關節炎管理概述」)

●(參見「Management of moderate to severe knee osteoarthritis」)

●(參見「Comorbidities that impact management of osteoarthritis」)

●(參見「成人未分類膝關節疼痛的評估」)

●(參見「成人疑似肌肉骨骼性膝關節疼痛的評估方法」)

定義

●輕度膝關節OA–輕度膝關節OA患者存在輕度或間斷性膝關節疼痛，但膝關節功能和生存質量相對不受影響。

●中度膝關節OA–中度至重度OA患者存在持續性疼痛，其功能、活動能力和生存質量受到顯著影響。(參見「Management of moderate to severe knee osteoarthritis」)

一般原則對於所有OA患者，應徹底評估其對疾病和治療方法的認知程度、既往治療史以及對當前治療的預期。如果患者有運動會加重OA或OA必然會逐漸加重等錯誤觀念，而醫生又沒有及時發現並糾正，則治療效果可能會受到影響。關於OA及其治療方法的患者教育可在門診期進行，還可提供相應的書面資料，並推薦患者瀏覽國家或風溼病學會網站的相關內容。設定切實、積極的治療效果預期可能會提高患者的依從性，尤其是對於需要改變生活方式的治療措施，並且顯示可影響治療結局[1,2]。OA的治療原則，包括患者教育、自我管理和目標設定，詳見其他專題。(參見「骨關節炎管理概述」，關於『一般原則』一節)

治療膝關節OA患者前應進行全面評估，還應定期監測治療療效。OA患者的監測和評估詳見其他專題。(參見「骨關節炎管理概述」，關於『監測和評估』一節)

根據臨床表現選擇治療方法膝關節OA患者可能有不同的類別，做出治療決策時必須考慮到這點。

我們的治療方法通常與專業組織發布的指南相一致[3-8]。

輕度膝關節OA — 非藥物治療或者再聯合局部治療或鎮痛藥(根據需要使用)可充分控制此類患者的症狀(流程圖 1)。

中/重度膝關節OA — 非藥物性幹預措施是此類患者的一線療法，重度疼痛患者對水中鍛鍊的耐受性通常比地面鍛鍊好(流程圖 2)。

應特別注意可能影響疼痛的關節外因素，如情緒障礙、疼痛災難化(pain catastrophizing)和睡眠障礙(參見「骨關節炎管理概述」，關於『影響療效的因素』一節)。可能還需要其他療法，包括口服非甾體類抗炎藥(nonsteroidal antiinflammatory drug, NSAID)、關節內注射類固醇、度洛西汀和手術。

OA僅累及膝關節或同時累及其他關節 — OA可能僅發生於膝關節，也可能同時累及多個關節。對於有症狀的多關節OA患者，最佳治療方式為優先考慮從整體水平而非關節層面治療疼痛。關節內類固醇注射、局部用NSAID或辣椒鹼以及膝關節支具等局部幹預措施可有助於減輕膝關節疼痛，但在整體上可能無法充分改善患者的OA症狀。

有共存疾病的患者 — 膝關節OA常伴有其他疾病，如心血管病、糖尿病、高血壓、肥胖、抑鬱和消化性潰瘍病。此外，老年患者中膝關節OA的患病率很高，但應注意其確診年齡通常較小(中位值55歲)，且大約2/3的患者不到65歲[9,10]。因此，選擇治療方案時應考慮最大程度減少不良事件，同時能使患者的功能和生存質量達到最佳。(參見「Comorbidities that impact management of osteoarthritis」)

輕度膝關節OA無論膝關節OA嚴重與否，非藥物幹預措施都是治療的核心，可聯合藥物治療(流程圖 1)。

治療持續時間取決於患者的需求，但通常推薦終身接受非藥物療法，以緩解症狀和防止關節進一步損害。

初始非藥物治療措施 — 輕度OA患者的非藥物幹預措施包括體育鍛鍊以及必要時減輕體重。

鍛鍊 — 我們推薦所有膝關節OA患者長期進行體育鍛鍊，以緩解疼痛和保護關節。膝關節OA治療的核心是鍛鍊以及在需要時減輕體重[1,2,4,11,12]。所有膝關節OA患者都應接受鍛鍊方面的指導，無論其年齡、影像學疾病嚴重程度、疼痛程度、功能水平和共存疾病如何。一項Cochrane系統評價納入了54項試驗，其中19項被認為存在「較低的偏倚風險」，其結論是有中等至高質量的證據表明，地面鍛鍊後可迅速改善膝關節疼痛和功能(中等程度)[11]。這種改善程度與NSAID相當[4]。不過，鍛鍊的益處不會持續很長時間，主要原因為患者對鍛鍊的依從性逐漸降低[12]。因此，應採取一些策略來提高患者的依從性，如讓患者了解OA和鍛鍊益處以及進行長期監測。(參見「骨關節炎管理概述」，關於『一般原則』一節和「骨關節炎管理概述」，關於『監測和評估』一節)

關於何種運動方式、強度、持續時間和頻率最佳，目前尚無有力證據[13]。在臨床實踐中，通常根據患者的具體表現個性化地確定其運動處方。我們會讓患者接受物理治療，以優化鍛鍊效果[14]。我們傾向於選擇衝擊力小的有氧身體訓練(如，步行、騎自行車、划船和深水跑)聯合下肢力量訓練，這樣可使大多數膝關節OA患者的各種損傷得到恢復。然而，選擇鍛鍊方式時還應考慮患者的活動能力、具體損傷(如，力量、關節活動度、有氧適能和平衡)和偏好[13]。雖然幾乎沒有研究證據表明跑步會導致膝關節OA進展，但一般不建議進行跑跳等對關節衝擊較大的運動，以避免進一步損傷關節，尤其是較嚴重的OA病例[15]。還可在鍛鍊計劃中加入拉伸或柔韌性鍛鍊，以增加膝關節活動度，尤其是針對膕繩肌的訓練，可避免或最大程度減少膝關節的屈曲攣縮[13,14]。

水中鍛鍊對膝關節疼痛、功能和僵硬也有一定的臨床效果，但與未治療對照組相比，其效果並不明顯[16]。水中鍛鍊的耐受性更好且引發不良事件的可能性更低，因此特別適合有重度疼痛和/或身體機能較差的患者。

我們認為還可將太極作為膝關節OA患者的康復治療，患者可根據自己的喜好來選擇。儘管考察太極長期效果的大型試驗有限，但現有試驗表明，鍛鍊12周後，太極對膝關節疼痛、身體機能以及減少使用止痛藥的效果與標準鍛鍊相當，且改善抑鬱的效果更好[17,18]。此外，對於老年膝關節OA患者，太極還可改善平衡能力以及降低跌倒風險[19]。

減輕體重 — 負重活動期間膝關節會承受很大的負荷，因此保持理想的體重對保護關節結構和改善症狀很重要。除了肥胖和超重對膝關節的力學影響以外，脂肪組織釋放的脂肪因子(如，瘦素和脂聯素)還會直接參與OA的炎性改變和軟骨損傷過程[20,21]。(參見「骨關節炎的發病機制」和「Comorbidities that impact management of osteoarthritis」, section on 『Obesity』)

我們鼓勵衛生保健專業人員諮詢現有的本地社區健康計劃，或將患者轉至營養科，以確保超重和肥胖患者得到最佳減重支持[22]。(參見「成人肥胖：治療概述」)

我們採用的減重方法為限制膳食熱量聯合體育鍛鍊，多項研究均支持該做法[23]。例如，IDEA試驗納入了454例超重和肥胖的膝關節OA患者，並將其隨機分為3組：限制膳食熱量+鍛鍊、只限制膳食熱量或只鍛鍊[24]。18個月後，限制膳食熱量+鍛鍊組患者的減重和疼痛改善情況最好，減重11.4%、疼痛評分降低約50%，38%的患者在試驗結束時自訴幾乎沒有疼痛。

此外，研究表明體重變化的百分比與關節症狀改善具有劑量-反應關係，體重減少10%以上時症狀改善更明顯[25]。合理的初始目標為6個月內減重5%-10%[26]，並應根據患者的具體情況對初始目標進行定期的再評估。

限制熱量可能導致去脂體重減輕和肌力減弱，尤其是老年人，因此應同時進行力量訓練以避免這些不良反應。關於減肥藥(如，奧利司他)和手術(如，胃旁路術)等其他幹預措施對OA的影響，目前尚未進行深入研究。(參見「成人肥胖：治療概述」)

非藥物治療的效果不充分 — 如果嘗試非藥物幹預措施後沒有獲得滿意的疼痛緩解，可同時或在之後給予藥物治療。由於輕度膝關節OA患者常有共存疾病，且其他全身治療的副作用相對較多，所以在這種情況下局部治療(表 1)是個不錯的選擇。

雖然OA病程較長，有關藥物治療長期(≥1年)效果的研究證據比較少[27]。

局部用NSAID — 對於病變僅限於膝關節或同時累及手部的輕度OA患者，考慮到關節的位置較表淺，我們建議局部用而非口服NSAID。一項Cochrane系統評價發現，大約有60%的患者在接受局部用NSAID後疼痛至少改善50%，其效果與口服NSAID相當且略優於局部用安慰劑[28]。局部用NSAID的全身吸收減少，因此引發胃腸道、腎臟和心血管毒性的風險遠低於口服製劑(局部用雙氯芬酸的全身性暴露是口服製劑的1/5-1/17)[29,30]。患者對局部用NSAID的耐受性也更好，最常報導的副作用是輕度皮疹。目前研究最多的藥物為雙氯芬酸凝膠或溶液以及酮洛芬，其用法為一日2-4次用於受累膝關節，直至症狀得到控制。我們最常用的製劑為雙氯芬酸凝膠，但選擇局部用製劑時還應考慮當地是否有藥物及其花費。

局部用辣椒鹼 — 對於僅膝關節或少數其他關節出現輕度OA的患者，如果其他治療無效或有禁忌證，我們建議給予局部用辣椒鹼。辣椒鹼是一種從紅辣椒中提取的物質，它可能通過下調疼痛感覺神經元上的TRPV1受體活性以及消耗P物質來緩解疼痛。連續使用辣椒鹼會導致痛覺纖維的敏感性降低以及痛覺刺激傳導受抑制。不過，關於辣椒鹼消耗P物質對減輕疼痛的作用，目前仍有爭議[31]。

關於局部用辣椒鹼對膝關節OA疼痛的效果，現有隨機對照試驗相對較少，大部分試驗的隨訪時間都較短(不超過12周)，總體方法學質量較好[32]。大多數研究都發現局部用辣椒鹼的效果優於安慰劑，其中一項研究顯示，辣椒鹼治療4周可使疼痛減輕33%，效果顯著優於安慰劑[33]。一項為期12周的多中心隨機試驗納入了113例患者，並將其分配至使用0.025%的辣椒鹼乳膏(一日4次)或安慰劑[34]。治療4-12周發現，辣椒鹼緩解疼痛的效果更好，醫生整體評估顯示，辣椒鹼組症狀改善的患者(81%)比安慰劑組多(54%)。

局部用辣椒鹼最常見的副作用為局部燒灼感，發生率超過50%。不過，這種症狀通常為輕中度，且會隨著繼續用藥逐漸改善。此外，局部用辣椒鹼不應接觸黏膜、擦傷的皮膚、眼睛或生殖器。兩組患者的全身不良反應發生率無顯著性差異。

中/重度膝關節OA中重度膝關節OA的治療詳見其他專題。(參見「Management of moderate to severe knee osteoarthritis」)

無效或益處不明的療法一些膝關節OA療法不被我們常規應用或推薦，因為缺乏足夠證據支持其廣泛應用，例如神經阻滯、神經消融、幹細胞注射和關節牽伸。此外，還有一些益處不明確的療法。然而，對於上文所述療法無效的患者，在考慮潛在危害、花費和患者偏好後，也可嘗試一些此類療法(見下文)以作為輔助治療措施。

鞋墊 — 一些證據表明，膝關節內側間室OA患者不應使用外側楔形鞋墊，故我們不推薦這種方法。但一項研究表明，外側脛股關節OA伴膝外翻的患者在使用內側楔形鞋墊後疼痛顯著改善，因此我們認為此類患者可使用內側楔形鞋墊[35]。然而，比較內側楔形鞋墊與外側楔形鞋墊的研究較少[36]。

外側楔形鞋墊顯示可適度減少膝關節內收力矩，從而減少膝關節內側負荷。然而，meta分析納入了設置有中立位鞋墊和無鞋墊對照組的試驗，其發現與對照組(中立位鞋墊)相比，外側楔形鞋墊並未使內側膝關節OA患者的疼痛出現有臨床意義的改善[36,37]。此外，一項隨機臨床試驗納入了200例輕度至中度內側膝關節OA患者，治療12個月後行MRI發現，在使用外側全長楔形鞋墊與平底鞋墊的患者中，內側脛骨軟骨量和股骨軟骨量減少以及骨髓病變範圍的改變並無差異[38]。

氨基葡萄糖和軟骨素 — 在臨床實踐中，我們不推薦所有患者常規使用這些補充劑，但也不會阻止想要使用此類藥物的患者，尤其是這些藥物可改善患者症狀時(鹽酸氨基葡萄糖除外，我們推薦不要使用該藥)。一些隨機試驗評估了氨基葡萄糖和軟骨素對膝關節OA的效果，但結果並不一致[39]。方法學可靠、規模較大研究的回顧性結果表明，鹽酸氨基葡萄糖對膝關節疼痛幾乎沒有作用，而劑量更大或純度更高的硫酸氨基葡萄糖(1500mg/d)或軟骨素(800mg/d)效果更好，與安慰劑相比其緩解症狀的作用較小，但具有統計學意義[40-43]。例如，一項廠商贊助的隨機試驗納入了604例有症狀的膝關節OA患者，隨訪6個月後發現，藥用級硫酸軟骨素減輕疼痛和改善功能的作用優於安慰劑(差異具有統計學意義)，且與塞來昔布相當[43]。這項研究中，軟骨素(800mg)、塞來昔布(200mg)或安慰劑的用法均為每晚1次。這項研究有一個重要的局限性，即不確定主要結局改善具有統計學意義時是否也具有臨床意義，該研究中的主要結局為治療前後疼痛視覺模擬評分法(visual analog scale, VAS，0-100mm)和Lequesne指數(疼痛和功能的綜合評分)的變化。此外，3組中獲得最小臨床重要改善(即，VAS疼痛評分改善20mm)的患者數量沒有差異。其他meta分析也表明，長期使用(2-3年)硫酸氨基葡萄糖(1500mg/d)和軟骨素(800mg/d)延緩OA結構性損傷進展的效果可能有限[44,45]。

多項研究證實了這些膳食補充劑具有很強的安慰劑效果。這在具有裡程碑意義的氨基葡萄糖/軟骨素幹預試驗(GAIT)中得到了最佳闡明，該試驗發現，無論患者使用安慰劑還是鹽酸氨基葡萄糖和/或軟骨素，大約都有60%患者疼痛至少減輕20%[46](參見「骨關節炎管理概述」，關於『影響療效的因素』一節和「骨關節炎管理概述」，關於『安慰劑效應的作用』一節)。另一項多中心隨機非劣性試驗納入了164例中度至重度膝關節OA患者，並將其隨機分配至接受硫酸軟骨素+氨基葡萄糖或安慰劑[47]。隨訪6個月後發現，安慰劑組的總體疼痛評分降低平均值(33%)顯著高於治療組(19%)。該研究的局限性包括樣本量較小以及軟骨素和氨基葡萄糖的劑量可能不足。不過，值得注意的是這些補充劑引發不良事件的風險很低，與安慰劑相當。由於現有數據相互矛盾且不確定，所以主要的OA指南都不強烈推薦使用氨基葡萄糖和軟骨素[3,5,48]。

其他營養補充劑 — 支持膝關節OA患者使用其他營養補充劑的證據有限。在臨床實踐中，我們常會嘗試使用魚油、薑黃素(薑黃的活性成分)和/或齒葉乳香(Boswelliaserrata)來減輕膝關節OA患者的症狀。不過，薑黃素的胃腸道吸收較差，因此通常首選可增加吸收和生物利用度的薑黃素補充製劑，如薑黃素與胡椒鹼或胡椒素(黑胡椒的一種成分)的複方製劑。

一項系統評價和meta分析納入了69項研究，評估了用於膝關節、手或髖關節OA的20種營養補充劑，發現與安慰劑相比有7種補充劑對短期(≤3個月)減輕疼痛有重要的臨床意義(效應量較大)，包括左旋肉鹼、碧蘿芷、薑黃素、齒葉乳香提取物、薑黃(Curcuma longa)提取物、百香果果皮提取物和膠原水解物[49]。但對於其中大多數補充劑，目前都只進行了少數小型研究，相關的證據質量不一(極低至中等)。另外6種補充劑優於安慰劑，其效果具有統計學意義但並尚不明確是否具有臨床意義，包括未變Ⅱ型膠原、鱷梨大豆未皂化物、甲磺醯甲烷、雙醋瑞因、氨基葡萄糖和軟骨素。報導了長期結局的試驗(6個月以上，n=17)發現，沒有哪種補充劑對疼痛的效果有臨床意義。Meta分析發現，這些補充劑的副作用風險並未超過安慰劑(雙醋瑞因除外)，但只有少數試驗考察了其安全性。還有一點值得注意，大多數試驗(64%)都接受了相關行業的資金支持，因此認為其偏倚風險較高或不明確(46%和44%)。

一項大型臨床試驗發現，與安慰劑相比，維生素D補充劑治療2年對疼痛和脛骨軟骨量變化並無益處[50]。一項研究評估了低劑量與大劑量魚油(分別為0.45g和4.5g ω-3脂肪酸)的臨床效果，隨訪2年後發現，低劑量組的疼痛和功能改善更大[51]。兩組的不良事件均較常見，尤其是胃腸道不適和返流等胃腸道事件(發生率均為60%左右)。研究還發現魚油對類風溼性關節炎有效，可能與二十碳五烯酸和二十二碳六烯酸的抗炎作用有關。但目前仍不明確魚油對OA是否有益。

還有有限的證據表明，植物類黃酮可能改善膝關節OA的症狀，這是一種有抗炎作用的天然化合物[52-54]。但有報導稱，一種名為Flavocoxid的特殊植物類黃酮會引起嚴重不良事件，包括肝損傷和過敏性肺炎，因此不推薦使用該藥。(參見「草藥和膳食補充劑的肝毒性」，關於『flavocoxid』一節)

阿片類物質 — 阿片類物質引發嗜睡、頭暈和噁心等副作用的風險相對較高，且長期使用可能有害，因此我們儘可能避免使用，尤其是老年患者。在臨床實踐中，我們僅將阿片類物質用於等待關節置換的重度疼痛患者(即，短期使用)。我們會給予控制症狀所需的最低劑量和最短持續時間，同時監測常見副作用。(參見「阿片類藥物用於治療慢性非癌症疼痛」)

多項針對膝關節OA患者的研究發現，阿片類物質的鎮痛效果與NSAID相似。一項meta分析發現，曲馬多以外的阿片類物質緩解疼痛的總體效應較弱(SMD -0.28，95%CI -0.35至-0.20)，具體表現為阿片類物質組與安慰劑組的VAS(0-10cm)差異僅有0.7cm[55]。膝關節功能改善也有限，每日嗎啡等效劑量不會影響功能改善。使用阿片類物質的患者更可能因不良事件退出試驗，也更可能出現副作用(發生率分別為6.5% vs 1.7%和22% vs 15%)[55]。一項網狀meta分析納入了至少為期8周的試驗，也未發現強效阿片類物質(氫嗎啡酮和羥考酮)、弱效阿片類物質(曲馬多)和NSAID的效果有差異[56]。此外，一項隨機試驗納入了240例存在慢性背痛或髖關節/膝關節OA疼痛的患者，非阿片類藥物與阿片類治療12個月後，疼痛相關功能並無差異[57]。

應用阿片類物質除了有一些已知風險和危害，還有一些數據提示OA患者使用曲馬多與死亡率增加有關。一項傾向評分匹配研究納入了88,902例OA患者的數據，在1年隨訪期間，曲馬多組的死亡率高於常用NSAID組(如萘普生)，HR為1.71，95%CI為1.41-2.07[58]。但這種結果容易出現適應證混雜，因為在傾向評分匹配前曲馬多組的並存疾病負擔高於NSAID組。

透明質酸 — 關節內透明質酸(hyaluronic acid, HA)製劑尚缺乏有力的療效證據，故不推薦使用[3,5,8,48]。關於黏性補充劑(即關節內透明質酸)治療症狀性膝關節OA的療效，一直存在爭議，各試驗和meta分析的數據也存在矛盾。大型高質量的雙盲試驗的證據表明，與關節內注射安慰劑相比，關節內注射透明質酸有較小的益處，但無臨床意義[59-61]。此外，關節內透明質酸的花費較高且可能有副作用，如疼痛發作和關節感染，但後者較罕見。

富血小板血漿 — 目前並無確鑿證據支持對膝關節OA患者注射富血小板血漿(platelet-rich plasma, PRP)，因此我們不推薦該方法。然而，越來越多證據表明該方法可改善OA症狀。與關節內注射安慰劑或透明質酸相比，關節內注射PRP後12個月，膝關節疼痛和功能顯著改善[62]。然而，早期研究的總體偏倚風險較高，以及不同研究中的注射次數(通常為1-4次)、注射間隔時間、PRP製備和注射量存在很大差異，因此現有證據仍顯不足[62]。與結構損傷更嚴重的患者(即，Kellgren-Lawrence分級≥3)相比，不太嚴重的OA患者是否可通過這些幹預措施獲益更多，目前也不明確。PRP治療OA的更多信息參見其他專題。(參見「骨關節炎的在研管理方案」，關於『富血小板血漿』一節)

對乙醯氨基酚 — 由於擔心對乙醯氨基酚(撲熱息痛)的安全性，以及逐漸認識到其對疼痛的效果微乎其微且沒有臨床意義[3,63-66]，我們在臨床實踐中不會使用對乙醯氨基酚治療膝關節OA。一項meta分析納入了10項試驗共3541例患者，發現有高質量證據表明，對乙醯氨基酚對疼痛的短期效果甚微且沒有臨床意義[65]。一項網絡meta分析比較了不同止痛藥對OA疼痛的效果，發現不同劑量對乙醯氨基酚的效果與安慰劑沒有差異(VAS上的差異為4mm；VAS：0-100mm)，進一步證實了上述結果[63]。對乙醯氨基酚引起損傷的風險隨劑量增加而升高，但治療劑量下也可能引發損傷，包括胃腸道出血、肝毒性、腎衰竭和心血管疾病[66]。由於其他治療疼痛和感冒症狀的常見非處方藥中常含有對乙醯氨基酚，所以應特別注意意外過量的風險。

經皮神經電刺激 — 關於經皮神經電刺激(transcutaneous electrical nerve stimulation, TENS)對OA的效果，現有數據並不一致[67]。其作用機制為門控理論，即大腦通過脊髓背角的突觸前抑制來調節傷害性刺激。一項Cochrane系統評價發現，由於大多數研究的方法學質量較差、樣本量較小以及各試驗間的異質性為中等或較高，所以關於TENS療效的證據尚不確切[67]。另一項試驗納入了203例參加教育和運動訓練計劃的患者，發現與假幹預相比，TENS、幹擾電流或短波透熱療法對疼痛和功能並無益處[68]。還有證據表明，TENS療法具有顯著的安慰劑效應[68,69]。

針刺 — 針刺治療OA的內容參見其他專題。(參見「Acupuncture」, section on 『Knee osteoarthritis』)

局部熱療 — 膝關節OA患者自己使用暖寶寶/熱水袋進行局部加熱可能會在短期內緩解疼痛[70-72]。一項小型隊列研究納入了膝關節OA患者，發現與只進行常規治療相比，同時應用局部熱療可使疼痛和失能改善更多[72]。

患者教育—UpToDate提供兩種類型的患者教育資料：「基礎篇」和「高級篇」。基礎篇通俗易懂，相當於5-6年級閱讀水平(美國)，可以解答關於某種疾病患者可能想了解的4-5個關鍵問題；基礎篇更適合想了解疾病概況且喜歡閱讀簡短易讀資料的患者。高級篇篇幅較長，內容更深入詳盡；相當於10-12年級閱讀水平(美國)，適合想深入了解並且能接受一些醫學術語的患者。

以下是與此專題相關的患者教育資料。我們建議您以列印或電子郵件的方式給予患者。(您也可以通過檢索「患者教育」和關鍵詞找到更多相關專題內容。)

●基礎篇(參見「患者教育：骨關節炎(基礎篇)」和「患者教育：關節炎和鍛鍊(基礎篇)」)

●高級篇(參見「Patient education: Osteoarthritis symptoms and diagnosis (Beyond the Basics)」和「Patient education: Osteoarthritis treatment (Beyond the Basics)」和「Patient education: Arthritis and exercise (Beyond the Basics)」)

學會指南連結部分國家及地區的學會指南和政府指南的連結參見其他專題。(參見「Society guideline links: Osteoarthritis」)

總結與推薦

●對於所有骨關節炎(OA)患者，應徹底評估其對疾病和治療方法的認知程度、既往治療史以及對當前治療的預期。關於OA及其治療方法的患者教育可在門診期進行，還可提供相應的書面資料。還應定期監測治療療效。(參見上文『一般原則』)

●膝關節OA患者可能有不同的類別，做出治療決策時必須考慮到這點(參見上文『根據臨床表現選擇治療方法』)：

•輕度膝關節OA–輕度膝關節OA患者存在輕度或間歇性膝關節疼痛，但膝關節功能和生活質量相對未受影響。非藥物治療或者再聯合局部治療或鎮痛藥(根據需要使用)可充分控制此類患者的症狀(流程圖 1)。(參見上文『輕度膝關節OA』)

•中/重度膝關節OA–中至重度OA患者存在持續性疼痛，其功能、活動能力和生存質量受到顯著影響。此類患者的一線療法也為非藥物性幹預措施，但通常還需要給予其他治療，包括口服非甾體類抗炎藥(NSAID)、關節內注射類固醇、度洛西汀，可能還需要手術(流程圖 2)。(參見上文『中/重度膝關節OA』)

•OA僅累及膝關節或同時累及其他關節–對於症狀性多關節OA患者，最佳治療方式為優先考慮整體而非關節層面緩解疼痛。(參見上文『OA僅累及膝關節或同時累及其他關節』)

•有共存疾病的患者–膝關節OA常伴有其他疾病(如，心血管疾病和糖尿病)；選擇治療方案時應考慮最大程度減少不良事件，同時使患者的功能和生存質量達到最佳。(參見上文『有共存疾病的患者』)

●我們推薦所有膝關節OA患者堅持長期體育鍛鍊，以緩解疼痛和保護關節(Grade 2B)。關於最佳的運動方式、強度、持續時間和頻率，目前尚無有力證據。我們傾向於選擇衝擊力小的有氧運動(如，步行、騎自行車、划船和深水跑)聯合下肢力量訓練。(參見上文『鍛鍊』)

●我們建議超重的膝關節OA患者限制膳食熱量並進行體育鍛鍊，以保護關節結構和改善症狀(Grade 2B)。我們鼓勵衛生保健專業人員諮詢現有的當地社區健康計劃，或將患者轉至營養科，以確保超重和肥胖患者得到了最佳減重支持。(參見上文『減輕體重』)

●對於病變僅限於膝關節或同時累及手部的輕度OA患者，我們建議初始治療選擇局部用NSAID，而不用口服NSAID(Grade 2C)。局部用NSAID的全身吸收減少，因此引發胃腸道、腎臟和心血管毒性的風險遠低於口服製劑。患者對局部用NSAID的耐受性也更好，最常報導的副作用為輕度皮疹。(參見上文『局部用NSAID』)

●對於僅膝關節或少數其他關節出現輕度OA的患者，如果其他治療無效或有禁忌證，我們建議給予局部用辣椒鹼(Grade 2C)。(參見上文『局部用辣椒鹼』)

●還有幾種方法可用於治療膝關節OA患者，但由於缺乏療效數據，我們通常不會常規使用這些方法。這包括一些益處不明確的療法。因此，對於上文所述療法無效的患者，也可嘗試一些此類療法(見下文)以作為輔助治療措施，其包括：

•鞋墊和鞋(參見上文『鞋墊』)

•氨基葡萄糖和軟骨素(參見上文『氨基葡萄糖和軟骨素』)

•其他營養補充劑(參見上文『其他營養補充劑』)

•阿片類物質(參見上文『阿片類物質』)

•透明質酸(參見上文『透明質酸』)

•富血小板血漿(PRP)(參見上文『富血小板血漿』)

•對乙醯氨基酚(參見上文『對乙醯氨基酚』)

•經皮神經電刺激(TENS)(參見上文『經皮神經電刺激』)

•針刺(參見上文『針刺』)

•局部熱療(參見上文『局部熱療』)

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英語版本

INTRODUCTIONEvidence-based approaches to the treatment of knee osteoarthritis (OA) include nonpharmacologic, pharmacologic, and surgical modalities targeted at relieving pain, improving joint function, and modifying risk factors for disease progression. Treatments to modify the course of the disease have not reached a threshold of efficacy to gain regulatory approval, despite numerous efforts.

There are multiple mechanisms that can contribute to the pain experience, and a holistic assessment of the patient is a paramount component of knee OA treatment. In addition, clinical decision-making is often influenced by specific patient and disease characteristics. This topic will provide an overview of the management of knee OA, with a focus on the management of mild knee OA. Separate topic reviews on OA as well as knee pain include the following:

●(See "Pathogenesis of osteoarthritis".)

●(See "Epidemiology and risk factors for osteoarthritis".)

●(See "Clinical manifestations and diagnosis of osteoarthritis".)

●(See "Overview of the management of osteoarthritis".)

●(See "Management of moderate to severe knee osteoarthritis".)

●(See "Comorbidities that impact management of osteoarthritis".)

●(See "Approach to the adult with unspecified knee pain".)

●(See "Approach to the adult with knee pain likely of musculoskeletal origin".)

●

DEFINITIONSThese definitions are based on the severity of the impact of the disease on the person rather than on radiographic severity in line with a person-centered approach to management and the fact that symptoms and radiographic findings are not necessarily well correlated and that imaging is not usually required for diagnosis [1]. (See "Overview of the management of osteoarthritis", section on 'Mechanisms of pain'.)

●Mild knee osteoarthritis – Patients with mild knee osteoarthritis (OA) have low levels of or intermittent knee pain with relatively well-preserved joint function and quality of life.

●Moderate/severe knee osteoarthritis – Patients with moderate to severe OA have persistent pain which significantly impairs functionality, activity participation, and quality of life. (See "Management of moderate to severe knee osteoarthritis".)

GENERAL PRINCIPLESAll patients with osteoarthritis (OA) should be thoroughly assessed with regard to their knowledge about the disease and treatment alternatives, previous experiences with treatment, and expectations of current treatment. The presence of misconceptions, such as that exercise will worsen OA or that OA will inevitably get worse, may attenuate the results of treatment if not properly identified and countered. Patient education about OA and its treatment options can occur during the clinical encounter and can be complemented by provision of written materials and referral to national or rheumatology association websites. Creating realistic and positive expectations for treatment efficacy may enhance adherence, especially to therapies that require lifestyle changes, and has been shown to positively influence treatment outcomes [2,3]. The management principles for OA, including education, self-management, and goal-setting, are discussed in detail separately. (See "Overview of the management of osteoarthritis", section on 'General principles'.)

The management of patients with knee OA should include a holistic assessment. Monitoring of the patient's response to therapy should also be done on a regular basis. A detailed discussion on monitoring and assessment of OA patients can be found elsewhere. (See "Overview of the management of osteoarthritis", section on 'Monitoring and assessment'.)

APPROACH BASED ON CLINICAL PRESENTATIONPatients with knee osteoarthritis (OA) may fall into different categories that must be considered when making treatment decisions.

Our management approach is generally consistent with guidelines developed by professional organizations [4-11].

Mild knee osteoarthritis — Nonpharmacologic therapies alone, focusing on education, exercise, and weight management, or in combination with topical therapies or analgesics on an as-needed basis are likely to provide adequate control of symptoms in this group of patients (algorithm 1).

Moderate/severe knee osteoarthritis — Nonpharmacologic interventions are the first-line therapy for this group of patients, and aquatic exercises are usually better tolerated than land-based exercises in patients with severe pain (algorithm 2). Special consideration should be given to extraarticular factors potentially contributing to pain, such as mood disturbances, pain catastrophizing, sleep problems, and chronic widespread pain (see "Overview of the management of osteoarthritis", section on 'Factors affecting response to therapy'). Other treatment alternatives may be required, including oral nonsteroidal antiinflammatory drugs (NSAIDs), intraarticular steroids, duloxetine, and surgery.

Knee osteoarthritis with one or more joints involved — OA can be localized in the knee only or occur concomitantly with OA in multiple joints. The best approach for managing patients with multijoint, symptomatic OA is to prioritize therapies that address the pain at the individual level and not at the joint level. Local interventions such as intraarticular steroid injections, topical NSAIDs or capsaicin, and knee braces may help with knee pain but are likely to be insufficient to provide adequate improvement in the patient's OA symptoms as a whole.

Patients with comorbidities — Knee OA is often comorbid with other conditions such as cardiovascular disease, diabetes, hypertension, obesity, depression, and peptic ulcer disease. In addition, knee OA is highly prevalent in the older adult population, although it is important to note that its diagnosis usually occurs earlier in life (median age 55 years) and around two-thirds of the patients are younger than 65 years [12,13]. Therapies should be chosen to minimize the potential for adverse events while optimizing function and quality of life. (See "Comorbidities that impact management of osteoarthritis".)

MILD KNEE OSTEOARTHRITISNonpharmacologic interventions are the backbone of knee osteoarthritis (OA) management, irrespective of OA severity, and can be used in combination with pharmacologic therapy (algorithm 1). The duration of therapy depends upon the individual patient's needs; however, lifelong treatment with nonpharmacologic therapies is generally recommended in order to relieve symptoms and prevent further joint damage.

Initial nonpharmacologic measures — Nonpharmacologic interventions in the management of patients with mild OA includes exercise and, when pertinent, weight loss.

Exercise — In all patients with knee OA, we recommend ongoing exercise for pain relief and joint protection. Exercise, alongside weight loss when indicated, is a core component of knee OA management [2,3,5,14,15]. All patients with knee OA should be counseled on exercise irrespective of age, radiographic disease severity, pain intensity, functional levels, and comorbidities. A Cochrane review of 54 trials, among which 19 were considered as "low risk of bias," concluded that there is moderate- to high-quality evidence suggesting that land-based exercise improves knee pain and function with moderate effect size immediately after treatment [14]. This magnitude of effect is comparable to that reported for oral nonsteroidal antiinflammatory drugs (NSAIDs) [5]. However, the benefits of exercise were not sustained in the long term, which is largely related to the decreasing adherence rates to the exercise program over time [15]. Strategies to improve adherence should be adopted, such as patient education about OA and the benefits of exercise and long-term monitoring. (See "Overview of the management of osteoarthritis", section on 'General principles' and "Overview of the management of osteoarthritis", section on 'Monitoring and assessment'.)

At present, there is no strong evidence on the best prescription of exercise modalities and dosage (ie, intensity, duration, and frequency) [16]. In clinical practice, exercise prescription is frequently personalized according to individual findings. We refer our patients for physical therapy to optimize the effectiveness of the exercise program [17]. We prefer a combination of low-impact aerobic fitness training (eg, walking, cycling, rowing, and deep-water running) and lower-limb strengthening exercises, which addresses the full spectrum of impairments in most patients with knee OA. Nevertheless, exercise choice should be also based on patient's mobility, specific impairments (eg, strength, range of motion, aerobic fitness, and balance), and preferences [16]. Exercises involving high impact on the joints such as running or jumping are usually discouraged in order to avoid further joint damage, especially in cases of more advanced OA, although research evidence demonstrating an association between running and progression of knee OA is scarce [18]. For those patients who already run or jog for exercise and develop mild symptoms of OA but wish to continue running, we advocate a load management approach with attention paid to factors such as rest days, running surface, distance and speed, and footwear, as well as building up muscle strength. Stretching or flexibility exercises, particularly of the hamstrings to avoid or minimize flexion contracture of the knee, can also be part of the exercise program to increase knee range of motion [16,17].

Aquatic exercise also has clinically relevant effects on knee pain, function, and stiffness, but the effects are small when compared with non-treatment controls [19]. This exercise modality is particularly useful for patients with severe pain and/or poor physical function due to its better tolerance and lower potential to cause adverse events.

We also consider Tai Chi as a treatment option for the rehabilitation of patients with knee OA, according to patients' preferences. Despite the limited number of large trials investigating the long-term effects of Tai Chi, it has been shown to be as effective as a standard exercise program after 12 weeks in terms of knee pain, physical function, and reduction in analgesic use, in addition to having greater improvement in depression [20,21]. Moreover, Tai Chi improves balance and is associated with a reduced falls risk in older patients with knee OA [22].

Weight loss — Because of the substantial load placed on the knees during weightbearing activities, maintaining an ideal body weight is critical to preserve joint structures and improve symptoms. In addition to the mechanical consequences of obesity and overweight to the joint, adipokines released by the adipose tissue such as leptin and adiponectin are directly involved in the inflammatory component of OA and cartilage damage [23,24]. (See "Pathogenesis of osteoarthritis" and "Comorbidities that impact management of osteoarthritis", section on 'Obesity'.)

We encourage health care professionals to consult available local community programs or refer patients to a dietitian to ensure that overweight and obese patients are offered optimal support to lose weight [25]. (See "Obesity in adults: Overview of management".)

Our approach of a combination of a calorie-restricted diet and physical activity to achieve weight loss is supported by several studies [26]. As an example, the IDEA trial randomized 454 overweight and obese adults with knee OA into one of three groups: diet plus exercise, diet alone, or exercise alone [27]. Participants in the diet plus exercise group had the highest percentage of weight lost (11.4 percent of body weight) and improvement in pain after 18 months, achieving a decrease in pain scores of approximately 50 percent, with 38 percent of patients reporting no or little pain at the end of the trial.

Moreover, a dose-response relationship between the extent of percentage change in body weight and improvement in joint symptoms has been demonstrated, with more robust effects achieved when at least a 10 percent reduction in body weight is attained [28]. A reasonable initial target is a 5 to 10 percent weight reduction within a six-month period [29], and initial goals should be reassessed periodically and individually for each patient.

Caloric restriction, particularly in order adults, may contribute to loss of lean mass and lead to muscle weakness and should, therefore, be combined with strengthening exercises to prevent these adverse effects. Other interventions such as anti-obesity drugs (eg, orlistat) and surgical approaches (eg, gastric bypass) are less well studied in the context of OA. (See "Obesity in adults: Overview of management".)

Inadequate response to nonpharmacologic measures — Pharmacologic therapy can be started in combination with or after a trial of nonpharmacologic interventions, if satisfactory pain relief is not achieved with these measures alone. Topical therapies (table 1) for the treatment of mild knee OA are particularly appealing due to the frequent presence of comorbid conditions in this patient population and the relatively common side effects of other systemic treatment options. Despite the chronic nature of OA, research evidence on the long-term efficacy (≥1 year) of pharmacologic therapies is limited [30]. Nonetheless, in our experience, topical NSAIDs, used either as needed or on a daily basis, may provide long-term benefits when combined with nonpharmacologic measures. Topical capsaicin, however, is less tolerated by patients due to the relatively high frequency of local side effects, including a local burning sensation. We do not use topical salicylates in our patients with OA.

Topical NSAIDs — We suggest topical nonsteroidal antiinflammatory drugs (NSAIDs) rather than oral NSAIDs for patients with mild OA localized to the knee or with concomitant hand involvement, given the superficial location of the joints in these cases. A Cochrane review found that about 60 percent of patients achieved at least 50 percent improvement in pain with topical NSAIDs, which was comparable to the effect obtained with oral formulations and slightly better than that observed with topical placebo [31]. The risk of gastrointestinal, renal, and cardiovascular toxicity is much lower with topical NSAIDs as compared with its oral formulation due to the reduced systemic absorption (5- to 17-fold lower for topical diclofenac compared with oral) [32,33]. The tolerability profile is also better with topical NSAIDs, with mild skin rashes being the most commonly reported side effect. The drugs studied with the most frequency were diclofenac gel or solution and ketoprofen, applied over the affected knee two to four times daily, for the duration necessary to control symptoms. We most commonly use diclofenac gel, but the choice of topical agent may vary according to local availability and cost.

Topical capsaicin — For patients with mild OA localized to the knee or a few other joints in whom other treatments are ineffective or contraindicated, we suggest topical capsaicin. Capsaicin is a substance derived from hot chili peppers with the potential to alleviate pain through the down-regulation of the TRPV1 receptor activity on nociceptive sensory neurons and the depletion of substance P. Continued use of capsaicin results in desensitization of nociceptive fibers and inhibition of pain stimulus transmission. However, the causative role of substance P depletion on pain reduction associated with capsaicin use has come into question [34].

There are relatively few randomized controlled trials investigating topical capsaicin treatment for knee OA pain, most with a short follow-up (up to 12 weeks) and overall good methodological quality [35]. In most studies, topical capsaicin was superior to placebo, with an overall 33 percent pain reduction after four weeks in one study, which was significantly greater than placebo [36]. In a 12-week randomized, multicenter trial, 113 patients received either capsaicin 0.025% cream four times daily or placebo [37]. Capsaicin provided greater pain relief after 4 to 12 weeks and a greater number of patients on capsaicin (81 percent) compared with placebo (54 percent) were improved based on physician's global evaluation.

Local burning sensation is the most common side effect of topical capsaicin and may occur in over half of patients. However, it is usually mild to moderate and improves with continued application. In addition, topical capsaicin should not come in contact with mucous membranes, abraded skin, eyes, or genital areas. Systemic adverse effects of capsaicin are not significantly higher compared with placebo. We prefer topical NSAIDs over capsaicin in our practice due to better tolerability and stronger evidence for efficacy.

MODERATE/SEVERE KNEE OSTEOARTHRITISThe management of moderate to severe knee osteoarthritis (OA) is discussed in detail separately. (See "Management of moderate to severe knee osteoarthritis".)

THERAPIES LACKING EFFICACY OR OF UNCERTAIN BENEFITThere are several approaches that have been used to treat patients with knee osteoarthritis (OA) that we generally do not routinely use or recommend due to lack of sufficient evidence base for widespread dissemination such as nerve blocks, nerve ablation, stem cell injections, and joint distraction. In addition, there are other therapies in which the benefit remains uncertain. It would be reasonable, however, to try some of the therapies discussed below as adjunctive measures for patients who do not respond to the approach described above after consideration of potential harm, cost, and patient preference.

Insoles — Due to the evidence indicating against the use of lateral wedge insole in medial compartment knee OA, we do not recommend their use. However, we consider medially wedged insoles for patients with lateral tibiofemoral OA and valgus deformity based on evidence from one study of significant improvements in pain for these patients [38]. Nevertheless, there are fewer studies investigating medial compared with lateral wedge insoles [39].

Lateral wedge insoles have been shown to modestly reduce the external knee adduction moment and thereby reduce medial knee joint loading. However, compared with control inserts (neutral soles), lateral wedge insoles provided no clinically significant improvement in pain in patients with medial knee OA, as examined in meta-analyses including trials with both neutral and no insole control [39,40]. Moreover, a randomized trial including 200 participants with mild to moderate medial knee OA found no differences between full-length lateral wedged insole and flat insole in medial tibial and femoral cartilage volume loss and change in size of bone marrow lesions on magnetic resonance imaging (MRI) over 12 months [41]. Another randomized trial that involved prescreening to select those patients more likely to respond to insoles (ie, those who showed a ≥2 percent reduction in the knee adduction moment with insoles and without patellofemoral OA) found that lateral wedge insoles reduced pain more than control insoles [42]. However, the effect of treatment was small and likely to be of clinical significance in only a minority of patients.

Glucosamine and chondroitin — In our clinical practice, we do not recommend these supplements routinely to all patients; however, we do not discourage their use for patients who are keen to take them, especially if symptomatic benefit is achieved with their use (except for glucosamine hydrochloride, which we recommend against). There have been conflicting results from randomized trials evaluating the efficacy of glucosamine and chondroitin in knee OA [43]. Results from reviews with larger, methodologically sound studies found negligible effects of glucosamine hydrochloride on knee pain, while higher doses or higher-grade formulations of glucosamine sulfate (1500 mg/day) or chondroitin (800 mg/day) showed more favorable results and may have a statistically significant but small effect on symptoms compared with placebo [44-47]. As an example, in an industry-sponsored randomized trial including 604 patients with symptomatic knee OA who were followed for six months, pharmaceutical-grade chondroitin sulfate was found to be statistically superior to placebo and similar to celecoxib in reducing pain and improving function [47]. Either chondroitin (800 mg), celecoxib (200 mg), or placebo was given once daily in the evening. One important limitation of the study is the uncertain clinical relevance of the statistical significance for the primary outcomes, which were based on a degree of change from baseline on a visual analog scale (VAS) for pain (0 to 100 mm) and the Lequesne index (a composite score of pain and function). Also, the number of patients who achieved the minimal clinically important improvement of 20 mm on the VAS for pain was not different among the three groups. Other meta-analyses also suggested that glucosamine sulfate (1500 mg/day) and chondroitin (800 mg/day) may have small effects in delaying structural progression of OA with long-term use (two to three years) [48,49].

A strong placebo effect has been demonstrated in the studies involving these dietary supplements. This is well illustrated by the landmark Glucosamine/Chondroitin Intervention Trial (GAIT), in which around 60 percent of participants experienced at least 20 percent pain reduction irrespective of whether they received placebo, glucosamine hydrochloride, chondroitin, or the combination of both [50] (see "Overview of the management of osteoarthritis", section on 'Factors affecting response to therapy' and "Overview of the management of osteoarthritis", section on 'Role of placebo effect'). In another multicenter randomized noninferiority trial, 164 patients with moderate to severe knee OA were treated with either chondroitin sulfate plus glucosamine or placebo [51]. At six months' follow-up, the mean reduction in the global pain score was significantly greater in the placebo group (33 percent) compared with the chondroitin sulfate plus glucosamine group (19 percent). Limitations of the study include the small size and potentially inadequate dosing of chondroitin and glucosamine. Whether some patient subgroups may benefit more from glucosamine than others has also been investigated, but no difference from placebo was found in any of the prespecified subgroups according to baseline pain severity, body mass index (BMI), gender, presence of inflammatory signs, or radiographic severity [52]. However, it is of note that the risk of any adverse event with these supplements is low and comparable to placebo. Due to these contradictory and still uncertain data, glucosamine and chondroitin are not strongly recommended by major OA guidelines [4,6,53,54].

Other nutritional supplements — There is limited evidence supporting the use of other nutritional supplements for knee OA. We do not routinely recommend nutritional supplements such as vitamin D, diacerein, avocado soybean unsaponifiables (ASU), and fish oil due to lack of clear evidence demonstrating a clinically important benefit from these supplements. In clinical practice, we often offer a trial other supplements such as curcumin (active ingredient of turmeric) and/or Boswellia serrata for knee OA patients for symptomatic relief and no evidence of increased risk of side effects compared with placebo [55]. This approach is based mostly on low-quality evidence. Curcumin is poorly absorbed by the gastrointestinal tract; curcumin supplements formulated to enhance absorption and bioavailability are usually preferred (eg, combinations of curcumin with piperine or bioperine, a constituent of black pepper).

A systematic review and meta-analysis of nutritional supplements for OA of the knee, hand, or hip including 69 studies (20 different supplements) found large and clinically important effects for seven supplements (L-carnitine, Pycnogenol, curcumin, Boswellia serrata extract, Curcuma longa extract, passion fruit peel extract, and collagen hydrolysate) compared with placebo in reducing pain in the short-term (≤3 months) [55]. Most of these supplements were investigated in only a limited number of small trials, and the quality of evidence for this finding was variable (very low to moderate). Six other supplements (undenatured type II collagen, avocado soybean unsaponifiables, methylsulfonylmethane, diacerein, glucosamine, and chondroitin) were statistically better than placebo, but it was unclear if the effects were clinically important. Among the trials reporting long-term outcomes (>6 months, n = 17), no supplement was found to have clinically important effects on pain. The meta-analysis found no increased risk of side effects of supplements compared with placebo, except for diacerein, although safety profile was investigated in only a limited number of trials. It is also important to note that most trials (64 percent) were industry funded and were considered at high or unclear risk of bias (46 and 44 percent, respectively).

In another study, vitamin D supplementation had no benefit over placebo on pain and change in tibial cartilage volume over two years in a large clinical trial [56]. A study assessing the efficacy of low- versus high-dose fish oil (0.45 and 4.5 g omega 3 fatty acids, respectively) on clinical outcomes found greater improvements in pain and function in the group receiving low-dose fish oil at two years [57]. Adverse events were common in both groups, particularly gastrointestinal events (around 60 percent in each group) such as gastrointestinal upset and reflux. Fish oil has also been studied in rheumatoid arthritis with positive results, probably through the antiinflammatory effects of the eicosapentaenoic and docosahexaenoic acids. However, its clinical benefit in OA is still unclear.

Limited evidence has also suggested that phytoflavonoids, a class of natural compounds with antiinflammatory properties, may have beneficial effects on knee OA symptoms [58-60]. Flavocoxid, a specific type of phytoflavonoid, has been associated with reports of serious adverse events related to liver injury and hypersensitivity pneumonitis, and its use is not recommended. (See "Hepatotoxicity due to herbal medications and dietary supplements", section on 'Flavocoxid'.)

Opioids — Due to the relatively high incidence of side effects such as drowsiness, dizziness, and nausea, and the potential to cause harm with long-term use, we avoid using opioids whenever possible, especially in the older adult population. In our clinical practice, we use opioids only in patients with severe pain awaiting joint replacement (ie, short-term use). We use it in the lowest dose and duration necessary to control symptoms and monitor common side effects. (See "Use of opioids in the management of chronic non-cancer pain".)

Several studies of patients with knee OA have found the efficacy of opioids with respect to pain reduction to be similar to that of NSAIDs. A meta-analysis revealed an overall small effect size (standardized mean difference [SMD] -0.28, 95% CI -0.35 to -0.20) of non-tramadol opioids on pain reduction, which corresponds to a difference of 0.7 cm on VAS (0 to 10 cm) between opioids and placebo [61]. Improvement in knee function was also small, and there was no influence of daily morphine equivalence dose on the benefits on function. Patients receiving opioids were more likely to drop out due to adverse events and more likely to experience side effects (6.5 versus 1.7 percent and 22 versus 15 percent, respectively) [61]. A network meta-analysis also did not demonstrate a difference in efficacy between potent opioids (hydromorphone and oxycodone), a less-potent opioid (tramadol), and NSAIDs in trials of at least eight weeks' duration [62]. In addition, a randomized trial including 240 patients with chronic back pain or hip or knee OA pain did not demonstrate a difference in pain-related function after 12 months of treatment with non-opioid versus opioid medications [63].

In addition to the known potential risks and harms of opioid use, there are some data to suggest an association between tramadol use and increased mortality among patients with OA. In a propensity score-matched study using data from 88,902 patients with OA, patients prescribed tramadol had a higher rate of mortality over the one-year follow-up period compared with commonly prescribed NSAIDs such as naproxen (hazard ratio 1.71 [95% CI 1.41-2.07]) [64]. These findings, however, may be susceptible to confounding by indication as the tramadol users had a higher comorbidity burden than patients receiving NSAIDs prior to propensity score matching.

Hyaluronans — The use of any intraarticular hyaluronic acid (HA) formulation is not widely recommended and not routinely used in our practice due to the lack of robust evidence demonstrating clinically relevant benefits over intraarticular placebo [4,6,9,53]. There has been a longstanding debate and conflicting data across trials and meta-analyses regarding the benefit of viscosupplementation (ie, intraarticular HA) for the treatment of symptomatic knee OA. The evidence from large, double-blinded, and high-quality trials indicates that intraarticular HA has a small, clinically irrelevant benefit over intraarticular placebo [65-67]. Moreover, intraarticular HA is associated with high costs and potential side effects such as pain flare-ups and joint infection, although the latter is a rare complication.

Platelet-rich plasma — Due to the lack of solid evidence for the recommendation of platelet-rich plasma (PRP) injection in patients with knee OA, we do not recommend its use. Nevertheless, evidence supporting its efficacy on OA symptoms has been growing rapidly. Injection of intraarticular PRP resulted in significant improvement in knee pain and function over intraarticular placebo and intraarticular HA up to 12 months post-injection [68]. However, evidence is still limited due to overall high risk of bias in previous trials and great variability between studies regarding the number of injections (generally one to four), interval between injections, preparation of the PRP, and volume injected [68]. There is also uncertainty regarding whether individuals with less severe OA may benefit more from this intervention compared with individuals with more advanced structural damage (ie, Kellgren-Lawrence grade [KLG] ≥3). Additional information on the use of PRP for OA can be found elsewhere. (See "Investigational approaches to the management of osteoarthritis", section on 'Platelet-rich plasma'.)

Acetaminophen — Due to safety concerns pertaining to acetaminophen (paracetamol) use and an increased awareness of its negligible and non-clinically significant effects on pain [4,69-72], we do not initiate treatment with acetaminophen for knee OA in our clinical practice. Data from a meta-analysis including 10 trials (3541 patients) revealed that there is high-quality evidence that paracetamol has only small, non-clinically meaningful benefits for pain in the short term [71]. This finding was further strengthened by a network meta-analysis comparing different analgesics for the treatment of OA pain, which demonstrated that paracetamol was not superior when compared with placebo irrespective of the dose (4 mm difference on a 0 to 100 mm VAS) [69]. The risk of harm of acetaminophen is usually higher with increasing dose but may also occur at doses within the therapeutic range, including gastrointestinal bleeding, liver toxicity, renal failure, and cardiovascular disease [72]. This is especially concerning due to the risk of unintentional overdose, as paracetamol is frequently combined with other common over-the-counter medications used to treat pain and cold symptoms.

Transcutaneous electrical nerve stimulation — Data on the efficacy of transcutaneous electrical nerve stimulation (TENS) in OA are conflicting [73]. Its mechanism of action is based on the gate-control theory, in which modulation of the nociceptive stimulus to the brain occurs through its presynaptic inhibition in the spinal cord dorsal horn. A Cochrane review found that the evidence regarding the efficacy for TENS was inconclusive based on the poor methodological quality of most studies, small sample sizes, and moderate to high heterogeneity between trials [73]. Another trial including 203 patients found no additional pain or function benefits from TENS, interferential currents, or shortwave diathermy compared with sham interventions in patients participating in an education and exercise training program [74]. In addition, there is evidence indicating a significant placebo component of the effect of TENS [74,75].

Acupuncture — The use of acupuncture in the management of OA is discussed elsewhere. (See "Acupuncture", section on 'Knee osteoarthritis'.)

Local heat and cold — Local application of heat using a heat pack or hot-water bottle as a self-management strategy may have beneficial short-term effects on pain in patients with knee OA [76-78]. In a small cohort study of patients with knee OA, local heat application in addition to routine management was associated with more improvements in pain and disability compared with routine management alone [78]. However, there are no robust clinical trials evaluating its effectiveness. Similarly, while not well studied, some patients may find icing of the joint useful temporarily to deal with a flare in pain or increase in swelling, for example, after an activity that has exacerbated symptoms.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Osteoarthritis (The Basics)" and "Patient education: Arthritis and exercise (The Basics)")

●Beyond the Basics topics (see "Patient education: Osteoarthritis symptoms and diagnosis (Beyond the Basics)" and "Patient education: Osteoarthritis treatment (Beyond the Basics)" and "Patient education: Arthritis and exercise (Beyond the Basics)")

SOCIETY GUIDELINE LINKSLinks to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoarthritis".)

SUMMARY AND RECOMMENDATIONS

●All patients with knee osteoarthritis (OA) should be thoroughly assessed with regard to their knowledge about the disease and treatment alternatives, previous experiences with treatment, and expectations of current treatment. Patient education about OA and its treatment options can occur during the clinical encounter and can be complemented by provision of written materials. Monitoring of the patient's response to therapy should also be done on a regular basis. (See 'General principles' above.)

●Patients with knee OA may fall into different categories, based on patient presentation rather than imaging, that must be considered when making treatment decisions (see 'Approach based on clinical presentation' above):

•Mild knee OA – Patients with mild knee OA have low levels of or intermittent knee pain with relatively well-preserved joint function and quality of life. Nonpharmacologic therapies alone or in combination with topical therapies or analgesics on an as-needed basis are likely to provide adequate control of symptoms (algorithm 1). (See 'Mild knee osteoarthritis' above.)

•Moderate/severe knee OA – Patients with moderate to severe OA have persistent pain which significantly impairs functionality, activity participation, and quality of life. Nonpharmacologic interventions are also first-line therapy, but other treatment alternatives are usually required, including oral nonsteroidal antiinflammatory drugs (NSAIDs), intraarticular steroids, duloxetine, and possibly surgery (algorithm 2). (See 'Moderate/severe knee osteoarthritis' above.)

•Knee OA with one or more joints involved – The best approach for management patients with multijoint, symptomatic OA is to prioritize therapies that address the pain at the individual level and not the joint level. (See 'Knee osteoarthritis with one or more joints involved' above.)

•Patient with comorbidities – Knee OA is often comorbid with other conditions (eg, cardiovascular disease, diabetes); therapies should be chosen to minimize the potential for adverse events while optimizing function and quality of life. (See 'Patients with comorbidities' above.)

●For all patients with knee OA, we recommend ongoing exercise for pain relief and joint protection (Grade 2B). There is no strong evidence on the best prescription of exercise modalities and dosage (ie, intensity, duration, and frequency). We prefer a combination of low-impact aerobic fitness training (eg, walking, cycling, rowing, and deep-water running) and lower-limb strengthening exercises. (See 'Exercise' above.)

●For patients with knee OA who are overweight, we suggest a calorie-restricted diet and exercise program to preserve joint structures and improve symptoms (Grade 2B). We encourage health care professionals to consult the available local community programs or refer patients to a dietitian to ensure that overweight and obese patients are offered optimal support to lose weight. (See 'Weight loss' above.)

●For patients with mild OA localized to the knee or with concomitant hand involvement, we suggest initial treatment with a topical NSAID rather than an oral NSAID (Grade 2C). The risk of gastrointestinal, renal, and cardiovascular toxicity is much lower with topical NSAIDs as compared with its oral formulation due to the reduced systemic absorption. The tolerability profile is also better with topical NSAIDs, with mild skin rashes being the most commonly reported side effect. (See 'Topical NSAIDs' above.)

●For patients with mild OA localized to the knee or a few other joints in whom other treatments are ineffective or contraindicated, we suggest topical capsaicin (Grade 2C). (See 'Topical capsaicin' above.)

●There are several approaches that have been used to treat patients with knee OA that we generally do not routinely use due to lack of data demonstrating efficacy. These include therapies for which the benefit remains uncertain; thus, some may be reasonable to try as adjunctive measures for patients who do not respond to the approach described above. These include:

•Insoles and footwear (see 'Insoles' above)

•Glucosamine and chondroitin (see 'Glucosamine and chondroitin' above)

•Other nutritional supplements (see 'Other nutritional supplements' above)

•Opioids (see 'Opioids' above)

•Hyaluronans (see 'Hyaluronans' above)

•Platelet-rich plasma (PRP) (see 'Platelet-rich plasma' above)

•Acetaminophen (see 'Acetaminophen' above)

•Transcutaneous electrical nerve stimulation (TENS) (see 'Transcutaneous electrical nerve stimulation' above)

•Acupuncture (see 'Acupuncture' above)

•Local heat (see 'Local heat and cold' above)

REFERENCES

Bedson J, Croft PR. The discordance between clinical and radiographic knee osteoarthritis: A systematic search and summary of the literature. BMC Musculoskelet Disord 2008; 9:116.

Hammer NM, Bieler T, Beyer N, Midtgaard J. The impact of self-efficacy on physical activity maintenance in patients with hip osteoarthritis - a mixed methods study. Disabil Rehabil 2016; 38:1691.

Damush TM, Perkins SM, Mikesky AE, et al. Motivational factors influencing older adults diagnosed with knee osteoarthritis to join and maintain an exercise program. J Aging Phys Act 2005; 13:45.

McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 2014; 22:363.

Fernandes L, Hagen KB, Bijlsma JW, et al. EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis. Ann Rheum Dis 2013; 72:1125.

National Clinical Guideline Centre (UK). Osteoarthritis: Care and Management in Adults, National Institute for Health and Care Excellence (UK), London 2014.

Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res (Hoboken) 2020; 72:149.